Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications.
Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications.
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DOI：
10.1002/humu.23192
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发表时间：
2017-04
期刊：
影响因子：
3.9
通讯作者：
Müller T
中科院分区：
文献类型：
--
作者：
Janecke AR;Xu R;Steichen-Gersdorf E;Waldegger S;Entenmann A;Giner T;Krainer I;Huber LA;Hess MW;Frishberg Y;Barash H;Tzur S;Schreyer-Shafir N;Sukenik-Halevy R;Zehavi T;Raas-Rothschild A;Mao C;Müller T
我们确定了两个不相关的血缘家庭，三个孩子受到罕见的先天性肾病综合征的关联诊断的第一天的生活，性腺功能减退症，产前检测肾上腺钙化，与先天性肾上腺功能不全的情况下。使用外显子组测序和靶向桑格测序，在编码鞘氨醇-1-磷酸裂解酶1的SGPL 1中鉴定了两个纯合截短突变，c.1513 C>T（p.Arg505*）和c.934 delC（p.Leu312 Phefs *30）。SGPL 1催化内源性和膳食鞘氨醇-1-磷酸（S1 P）的不可逆降解，这是鞘脂catenin的最后一步，也是其他磷酸化长链碱基的不可逆降解。S1 P是参与血管生成、血管成熟和免疫的细胞内和细胞外信号分子。通过液相色谱-串联质谱法测定，患者血液和成纤维细胞中SGPL 1底物、S1 P和鞘氨醇的水平显著增加。血管改变存在于患者的肾活检中，与在Sgpl 1敲除小鼠中观察到的变化一致，所述变化与血管成熟中的发育缺陷相容。总之，SGPL 1功能丧失与先天性肾病综合征、肾上腺钙化和性腺功能减退症有关。
We identified two unrelated consanguineous families with three children affected by the rare association of congenital nephrotic syndrome diagnosed in the first days of life, of hypogonadism, and of prenatally detected adrenal calcifications, associated with congenital adrenal insufficiency in one case. Using exome sequencing and targeted Sanger sequencing two homozygous truncating mutations, c.1513C>T (p.Arg505*) and c.934delC (p.Leu312Phefs*30), were identified in SGPL1 encoding sphingosine-1-phosphate lyase 1. SGPL1 catalyzes the irreversible degradation of endogenous and dietary sphingosine-1-phosphate (S1P), the final step of sphingolipid catabolism, and of other phosphorylated long-chain bases. S1P is an intra- and extracellular signaling molecule involved in angiogenesis, vascular maturation, and immunity. The levels of SGPL1 substrates, S1P and sphingosine were markedly increased in the patients’ blood and fibroblasts, as determined by liquid chromatography-tandem mass spectrometry. Vascular alterations were present in a patient’s renal biopsy, in line with changes seen in Sgpl1 knockout mice that are compatible with a developmental defect in vascular maturation. In conclusion, loss of SGPL1 function is associated with congenital nephrotic syndrome, adrenal calcifications, and hypogonadism.